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Updated: Mar 18, 2026

Measuring Single-Cell Mitochondrial DNA Copy Number and Heteroplasmy Using Digital Droplet Polymerase Chain Reaction
Published on: July 12, 2022
A U-Shaped Association Between Blood mtDNA Copy Number and Risk of Type 2 Diabetes
Xinhao Huang1, Zijian Tian2, Ying Pan3,4
1School of Public Health, Guangzhou Medical University, Guangzhou, China.
Objective:
mtDNA copy number (CN) reflects mitochondrial function, but prior studies have reported inconsistent associations with type 2 diabetes risk, ranging from inverse to positive or null findings. We hypothesized that mtDNA-CN is nonlinearly associated with incident type 2 diabetes.
Research Design And Methods:
We included 34,835 adults without diabetes from the Kunshan Aging Research With E-Health (KARE) cohort and 289,338 from the UK Biobank (UKB). Associations between blood mtDNA-CN and incident type 2 diabetes were evaluated using Cox proportional hazards and restricted cubic spline models stratified by age.
Results:
A U-shaped association was observed in the KARE cohort (P < 0.001), in which the hazard ratios (95% CIs) across increasing mtDNA-CN quartiles were 1.00 (reference), 0.94 (0.88-1.00), 0.85 (0.79-0.91), and 0.93 (0.87-1.00). In contrast, the UKB cohort exhibited a predominantly inverse linear trend. Age-stratified analyses revealed that this U-shaped association was particularly evident in younger participants (aged <65 years in KARE and <50 years in UKB), indicating elevated diabetes risk at both low and high mtDNA-CN levels. Additionally, mtDNA-CN declined with age in both cohorts, with an accelerated decrease beyond ∼65 years in KARE and ∼50 years in UKB.
Conclusions:
Blood mtDNA-CN showed a U-shaped association with incident type 2 diabetes in younger individuals.
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